In the US, bladder cancer is the fourth most common cancer in men and the eighth most common cancer in women. The clinical course in urinary bladder cancer has been difficult or impossible to predict: Unfortunately, recurrence, invasion, and metastasis, even after a seemingly successful treatment at early stage, are characteristic of bladder cancer. Our long-term goal is the identification of the alterations that are functionally critical for tumorigenesis and progression that will lead to more reliable patient stratification and outcome prediction and development of novel therapies. We have recently used a combination of genetic approaches to identify genes that may be functionally involved in the progression of bladder cancer. Thromboxane synthase (TXAS) was among the genes identified based upon its overexpression in a bladder cancer. Our preliminary data demonstrate that TXAS mRNA and protein are overexpressed in human bladder cancer and bladder cancer-derived cell lines. The frequency of TXAS overexpression is highest in high grade (G3) and late stage (T4) minors. We further determined that the Thromboxane A2 (TP) receptors are overexpressed in human bladder cancer and cell lines. Based upon our observations, we hypothesize that TXA2 contributes to metastatic bladder cancer via its control on cell proliferation, migration, and angiogenesis. We believe that TXA2-regulated pathways function in autocrine as well as paracrine pathways that affect the cancer cell and endothelial cells, respectively. We further hypothesize that inhibition of TP receptor signaling may provide a new therapeutic target for the treatment of bladder cancer. In this exploratory (R21) proposal, we will use pharmacological and molecular approaches to elucidate TXAS and TP receptor function in vitro and in vivo. Specifically, we will determine the effects of TP receptor antagonists or agonists and TXAS inhibitors on growth, migration, invasion of bladder cancer cells. These studies will be complemented by molecular loss of function and gain of function studies. We will evaluate clinical samples to determine whether the expression of TXAS and TP receptors is correlated with aggressive human bladder cancer. Collectively, these studies have the potential to reveal a new approach for the treatment of bladder cancer. [unreadable] [unreadable]